Sterilization process design for a medical adhesive

ABSTRACT

Medical devices, including medical adhesives, need to be sterile before application to a patient. A dry heat sterilization process can sterilize medical adhesives for patient application. The dry heat sterilization process can be validated for particular equipment arrangements and medical adhesives being utilized.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/775,014, filed Feb. 22, 2013, titled STERILIZATION PROCESS DESIGN FORA MEDICAL ADHESIVE, which claims the benefit under 35 U.S.C. §119(e) asa nonprovisional of U.S. Provisional Application No. 61/601,718, filedFeb. 22, 2012, titled STERILIZATION PROCESS DESIGN FOR A MEDICALADHESIVE, the entirety of each of which is incorporated herein byreference and made a part of this specification.

BACKGROUND

1. Field

This disclosure generally relates to sterilization of medical devices,and in particular, to sterilization of medical adhesives.

2. Description of the Related Art

Current treatments for varicose veins can in some cases can carry a highmorbidity, be ineffective, and/or be very painful, leaving the patientsout of commission for quite some time. A closure system for varicoseveins can compose several different components within a kit, eachrequiring sterilization.

SUMMARY

The closure system kit can be sterilized by using Ethylene Oxide.However, in some cases, this process is not effective for fluids such asmedical adhesives in the kit. Therefore, a new process is needed toefficiently sterilize a medical adhesive, such as a cyanoacrylatecomposition for treating, among other things, venous insufficiency.Proper sterilization of the medical adhesive decreases the risk ofinfection, allows patients to be back on their feet as soon as possible,as well as having a relatively painless treatment process of varicoseveins. A novel system and method for sterilization of medical adhesivesis disclosed herein.

The sterilized medical adhesive disclosed herein can be used in amedical device including a syringe filled with the medical adhesive thatis systematically introduced into the treated vein via catheter. Adispenser gun is attached to the syringe in order to regulate preciselyhow much adhesive is dispensed with each pull of the trigger. Prior touse in the medical device, the adhesive is mixed and packaged in, forexamples, 4 ml vials. In some embodiments, upon packaging in, forexample, the 4 ml vials, the adhesive can be sterilized. In someembodiments, the vials can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ml orlarger.

In some embodiments, a method of sterilization is first selected. Afterthe method is selected, proper parameters can be chosen for the specificprocess in order to produce a sterile product. After establishing avalidated sterilization process, lots of medical adhesive can beconsistently sterilized in order to achieve first demand. With propermaintenance and monitoring, the process can be used until the loadingconfiguration or specifications of the medical adhesive are changed.

In some embodiments, the medical adhesives can be sterilized beforebeing packaged with the rest of a medical device's components in, forexample, a kit. The sterilization process can adhere to AmericanNational Standards Institute (ANSI) standards. This process can beexecuted once to fulfill the first demand and therefore can produce alot size that accommodates this. This process can also be repeatedreliably for multiple orders. The adhesive can then be tested to ensurethat it performs to clinical and/or technical standards. Thetemperatures and durations for sterilization can be varied.

In accordance with embodiments disclosed herein, there is provided amethod for sterilizing a medical adhesive. The method comprisesenclosing the medical adhesive in a first housing, the first housingconfigured to seal the medical adhesive. The method further comprisespositioning the first housing with the medical adhesive in a tray, thetray configured to secure the first housing in a first predeterminedposition on the tray. The method further comprises positioning the traywith the first housing on an oven rack, the oven rack inside an oven.The method further comprises operating the oven at a predeterminedtemperature profile over a time duration to heat the medical adhesive toabout the predetermined temperature profile over the time durationsufficient to sterilize the medical adhesive, wherein the predeterminedtemperature profile includes a temperature range of about 110° C. toabout 120° C. and the time duration includes about 2 hours plus aramp-up time of about 40 minutes, wherein following the sterilizationprocess a post-sterilization viscosity of the medical adhesive is withinabout 5% of the pre-sterilization viscosity of the medical adhesive.Some embodiments may include one or more of the following features:enclosing a biological indicator in a second housing, the second housingconfigured to seal the biological indicator, the biological indicatorconfigured to indicate whether sterilization has been achieved;positioning the second housing with the biological indicator in thetray, the tray configured to secure the second housing in a secondpredetermined position on the tray; wherein the biological indicator isenclosed in the second housing with the medical adhesive, and whereinthe medical adhesive substantially surrounds the biological indicator;enclosing the medical adhesive in a first plurality of housings, thefirst plurality of housings configured to seal the medical adhesive;positioning the first plurality of housings with the medical adhesive inthe tray, the tray configured to secure the first plurality of housingin a first plurality of predetermined positions on the tray; wherein thefirst plurality of housing are heated to substantially a sametemperature over the time duration; wherein the first plurality ofpredetermined positions start at a center of the tray and radiate towardthe perimeter as the first plurality of housing are positioned in thetray to help provide the same temperature over the time duration;enclosing a substance not for patient application in a second pluralityof housings, the second plurality of housings configured to seal thesubstance; positioning the second plurality of housings with thesubstance in the tray, the tray configured to secure the secondplurality of housing in a second plurality of predetermined positions onthe tray; wherein the second plurality of predetermined positions aresubstantially at a perimeter of the tray; and/or wherein the medicaladhesive comprises a cyanoacrylate.

In accordance with embodiments disclosed herein, there is provided amethod for sterilizing a medical adhesive. The method comprisesenclosing the medical adhesive in a first housing, the first housingconfigured to seal the medical adhesive. The method further comprisespositioning the first housing with the medical adhesive in a tray, thetray configured to secure the first housing in a first predeterminedposition on the tray. The method further comprises positioning the traywith the first housing on an oven rack, the oven rack inside an oven.The method further comprises operating the oven at a predeterminedtemperature profile over a time duration to heat the medical adhesive toabout the predetermined temperature profile over the time durationsufficient to sterilize the medical adhesive, wherein the predeterminedtemperature profile includes a temperature range of about 110° C. toabout 120° C. and the time duration includes about 2 hours.

The foregoing is a summary and thus contains, by necessity,simplifications, generalization, and omissions of detail; consequently,those skilled in the art will appreciate that the summary isillustrative only and is not intended to be in any way limiting. Otheraspects, features, and advantages of the devices and/or processes and/orother subject matter described herein will become apparent in theteachings set forth herein. The summary is provided to introduce aselection of concepts in a simplified form that are further describedbelow in the Detailed Description. This summary is not intended toidentify key features or essential features of any subject matterdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features of the present disclosure will becomemore fully apparent from the following description, taken in conjunctionwith the accompanying drawings. Understanding that these drawings depictonly some embodiments in accordance with the disclosure and are,therefore, not to be considered limiting of its scope, the disclosurewill be described with additional specificity and detail through use ofthe accompanying drawings.

FIG. 1A illustrates an embodiment of a load configuration in a tray.

FIG. 1B illustrates an embodiment of a load configuration in a tray.

FIG. 1C illustrates an embodiment of a load configuration in a tray.

FIG. 2 illustrates an embodiment for placement of thermocouples on abaking sheet.

FIG. 3 illustrates an embodiment of a load configuration in a tray.

FIG. 4 illustrates an embodiment of a load configuration in a tray withone type of biological indicator.

FIG. 5 illustrates an embodiment of a load configuration in a tray withtwo types of biological indicators.

FIG. 6 illustrates a process flow diagram of an embodiment of a processqualification procedure.

FIG. 7 illustrates a graph showing representative temperature profilesfor an embodiment of a load configuration during a sterilizationprocess.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description and drawings are not meant to be limiting. Otherembodiments may be utilized, and other changes may be made, withoutdeparting from the spirit or scope of the subject matter presented here.It will be readily understood that the aspects of the presentdisclosure, as generally described herein, and illustrated in theFigures, may be arranged, substituted, combined, and designed in a widevariety of different configurations, all of which are explicitlycontemplated and make part of this disclosure.

The headings provided herein are for convenience only and do notnecessarily affect the scope or meaning of the claims.

In some embodiments, a customized sterilization process is designed tobe validated per ANSI standards. First, a proper process can be selectedto sterilize the product. In some embodiments, dry heat sterilizationcan be used. In addition to the type of sterilization, a method fordetermining if the resulting product would be sterile or not can beselected. For this determination, Biological Indicators (BI's) can beused. However, there are many different choices to choose from.

Second, parameters can be evaluated in order to choose the mostefficient cycle time. In some embodiments, the cycle time can vary fromabout 1-8 hours, including about 2-7 hours, including about 1, about 2,about 3, about 4, about 5, about 6, about 7, or about 8 hours, includingranges bordering and the foregoing values. The temperatures can varyfrom about 100 to about 200° C., including about 100 to about 120° C.,including about 110 to about 120° C., including about 110 to about 140°C., including about 120 to about 130° C., including about 120 to about180° C., including about 140 to about 160° C., including about 100,about 105, about 110, about 115, about 120, about 125, about 130, about135, about 140, about 145, about 150, about 155, about 160, about 165,about 170, about 175, about 180, about 185, about 190, and about 195°C., including ranges bordering and the foregoing values. Thesterilization cycle can be performed in one 8-hour workday, or shorteror longer time periods. Tests can have a Biological Indicator in theoven chamber that can indicate whether the process is adequate for thesterilization of the medical adhesive. The process that uses the leastamount of heat for the shortest amount of time and passes a sterilitytest can be selected in some embodiments. Having a shorter amount oftime while passing the sterility test can help achieve patient benefitsas discussed herein with minimal costs.

Further, not to be limited by theory, but using the least amount of heat(or temperature) necessary to sterilize the medical adhesive helpsprevent curing of the medical adhesive. In certain embodiments, athigher temperatures, a medical adhesive, such as a medical adhesive withcyanoacrylates, can lose viscosity when exposed to higher temperatures.Keeping the sterilization temperatures low, such as, for example, withnominal parameters as discussed herein without requiring a relativelylong heating time, helps prevent the loss of viscosity and preventcuring in some medical adhesives. In some embodiments, followingsterilization the difference between the viscosity of the adhesive iswithin about 200 cp, 150 cp, 100 cp, 75 cp, 50 cp, 40 cp, 30 cp, 25 cp,20 cp, 15 cp, 10 cp, 5 cp, 2 cp, 1 cp or less compared to thepre-sterilization viscosity of the adhesive. In some embodiments,following sterilization the difference between the viscosity of theadhesive is within about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,or less compared to the pre-sterilization viscosity of the adhesive.Further systems and methods for treatment of venous insufficiency andother conditions that can be used or modified for use with sterilizationsystems and methods as described herein can be found, for example, inU.S. Pub. No. 2010/0217306 A1 to Raabe et al., which is herebyincorporated by reference in its entirety.

Once the process and parameters have been determined, the process can bevalidated per ANSI standards. ANSI can involve a documented installationqualification, operation qualification and performance qualification.Once all three of those documents are written and performed, the processcan be validated and a complete lot of medical adhesive will be able toundergo the sterilization process. In some embodiments, the processdescribed herein can produce the following: (A) One or more sterilizedlots of medical adhesive; (B) A validated sterilization process that iscapable of being performed in the future; (C) A process that can beexecuted in one 8-hour workday.

To maintain sterility (prevent recontamination) after the sterilizationprocess, the medical adhesive can be packaged into a sterile barrier,such as, for example, vials prior to sterilization as discussed herein.The sterile barrier can withstand mechanical stresses such as stressesthat arise during shipping and handling. In some embodiments, thesterile barriers (e.g., vials) can resist applications of torque rangingfrom about 4 to about 24 inch-pounds, including about 8 to about 16inch-pounds, including ranges bordering and the foregoing values. Thesterile barrier is able to maintain sterility of the medical adhesivefor about one-half to about 2 years, including about 1 year, includingranges bordering and the foregoing values, after sterilization asdiscussed herein.

Sterilization Processes

Sterilization is the process of killing or removing microorganisms froma product to help ensure that it is sterile. In some embodiments,sterilization may include one, two, or more of dry heat sterilization,moist heat sterilization (steam), sterilization using electromagneticenergy (including, for example, optical, RF, ultrasound, and microwaveenergy) and/or gas sterilization, e.g., with Ethylene Oxide (ETO). Insome embodiments, electromagnetic energy sterilization could precede orfollow heat sterilization. Each process may have varying parameters,which can result in highly customizable sterilization solutions for eachindividual device.

Dry heat sterilization can sterilize small objects and can involveinexpensive equipment. In some embodiments, the parameters include at orabout 170° C. for one hour or 140° C. for three hours. The total cycletimes can be about twice as long (e.g., two hours or six hours,respectively) due to the ramp up and cool down of the oven and thedevices to be subjected to the process.

In some embodiments, there are several advantages when choosing dry heatas the primary mode of sterilizing a device. Dry heat sterilizationinvolves a process that is nontoxic. The setup can be simple to allowfor implementing a process that can specialize for a single device in acost effective manner. Because of these advantages, dry heat is apopular solution for small companies that are interested in low volumeproduction. However, dry heat sterilization can be applied on a largecommercial scale. Due to the high temperatures, dry heat should bechosen for objects that can withstand such an environment for anextended period of time. The slow rate of heat penetration and microbialkilling may make this a time-consuming method that is not suitable forsome materials.

For products that cannot be exposed to long periods of hightemperatures, moist heat sterilizations can provide an option thatoperates at a relatively lower temperature of approximately 121° C., forexample. Because there is moisture in the air, the heat is moreeffective at killing the bacteria present on the device.

Just like dry heat sterilization, moist heat provides a process in whichtwo variables can be controlled: temperature and time. Due to the lowertemperature and shorter cycle times, hospitals and other healthcarefacilities have steam sterilizers. These sterilizers can be used forquick sterilization of reusable equipment as well as liquids/fluids thatare not affected by the heat or moisture.

ETO can provide the ability to sterilize a kit containing many differentcomponent, which sets it apart from dry and moist heat. However, insteadof having two parameters to regulate, there are four. These includetime, temperature, heat, and ETO gas concentration/distribution. Sinceheat may be not the primary parameter for killing the bacteria, theprocess works with the penetration of the gas doing the work. This maylimit the materials that can be sterilized with ETO because manymaterials cannot be easily penetrated.

Each of these three processes provides their respective advantages anddisadvantages and therefore, may be used in parallel for differentcomponents of a medical device.

Biological Indicators

Biological Indicators (BIs) can be used to monitor the efficacy ofsterilization processes for medical products. BIs contain high numbers,generally 10⁴ to 10⁶, of bacterial endospores that are highly resistantto the sterilization process for which they are designed for. The sporesof bacteria are placed on a vehicle that is used to transport thebacteria through the sterilization process in order to determine theefficiency of the process. In some embodiments, the spores aretransported through the sterilization process via a suspension or asolid material such as a strip. BIs are the process indicators thatdirectly monitor the lethality of a given sterilization process, havedemonstrated resistance to the sterilization agent, and/or are moreresistant than the bioburden found on medical devices.

There are several different kinds of BIs depending on the applicationand the sterilization process that is to be monitored. Just likesterilization process selection, which BI to select can contribute tothe overall effectiveness of the process. Some common types of BIsinclude spore strips, mini spore strips, spore discs, self contained,spore ampoules, spore suspensions as well as custom spore solutions.

Biological indicators are designed to test worst case scenarios andtherefore can be placed in the hardest to reach places within thedevice. For example, if the device to be sterilized is a solid, hollowpiece of plastic, the BI can be placed inside the thickest part of thedevice to help ensure that it represents the worst case scenario. Forthis example, a spore strip can be used due to its ability to be securedto the inside of the part and also since it is the cheapest of theavailable BIs. Discs and mini spore strips may be used when space is anissue and a standard strip will not suffice. Spore ampules andsuspensions may be used for monitoring the sterilization of liquids,where a solid BI may absorb too much of the liquid and fall apart.

Once a medium is chosen, there are several species of bacteria availableto monitor specific sterilization processes. In some implementations,bacillus atrophaeus may be used to monitor dry heat and ETO whilegeobacillus stearothermophilus may be used for steam. Along withspecies, each BI can be tailored to operate within a temperature rangeand can be researched before selecting the one to monitor thesterilization process.

Due to having living bacteria within the BIs, BIs should be handled withcare and properly stored. In some embodiments, before use, they may bestored between about 0 to about 10° C., including about 2 to about 8°C., including about 1, about 2, about 3, about 4, about 5, about 6,about 7, about 8, and about 9° C., including ranges bordering and theforegoing values. After the BIs are subjected to the sterilizationcycle, they can be sent to a lab to undergo testing for bacterialgrowth. This involves an incubation period ranging from, about 1 toabout 10 days, including about 2 to about 7 days, including rangesbordering and the foregoing values, depending on the exact product used.After incubation, the BIs are compared to the negatives/controlsprovided from the manufacturer to check for growth. Generally, a colorchange is triggered by bacterial growth and therefore can represent afailed sterilization process.

Validation of Sterilization Processes

Once an appropriate sterilization process is selected along with asuitable type of BI, the sterilization process can be validated. Oncevalidated, the process is deemed sufficient at sterilizing the productssubjected to it and may be repeatable indefinitely when monitoredproperly. There are several components to the validation to help ensureall aspects of the process are regulated and operating per themanufacturer's instructions. The three main sections are theInstallation Qualification (IQ), the Operation Qualification (OQ), andthe Performance Qualification (PQ).

IQ can help ensure that all equipment is installed as specified withinthe user's manual. This can include utilities such as water, electrical,steam, and air. Also involved is the overall construction andconnections of the equipment to be used. All piping and wiring can becarefully inspected for discontinuities that could negatively affect theperformance of the equipment. Pre-determined construction andinstallation parameters can be assessed once installation permits areobtained.

Once the equipment has been inspected and documented, OQ can help ensurethat it is operating correctly. OQ can include testing the equipmentover its pre-defined and installed operating range to verify consistentperformance. This can include all controls, alarms, and monitoringdevices. OQ can include monitoring and documenting how the chamber heatsup and is distributed throughout it. Reproducible heating throughout thechamber can be demonstrated by performing three empty chamber cycles.

Once the equipment has been installed and is operating correctly,performance qualification can be performed. PQ can represent actual lotsundergoing the sterilization process that are tested for bacterialgrowth. Four total cycles are to be completed in some embodiments. Threeof these cycles are half cycles and the last is a full cycle. Thereasoning for the half cycles comes from the overkill method. If a halfcycle test properly sterilizes the product, then it is with much morecertainty that a full cycle will substantially eliminate of bacterialgrowth. The half cycles can be performed at the minimum, nominal, andmaximum parameter settings. Therefore, the machine can be validated torun within a window, making the target parameters easier to control andregulate.

The cycles can be tested using a full load of medical adhesive as wellas BIs distributed throughout. Once the four cycles are done, the BIscan be checked for bacterial growth. Every single BI that is subjectedto the sterilization process should produce a negative result whentested for bacterial growth in order for PQ to be considered complete.

Once the IQ, OQ, and PQ are completed the process is considered to bevalidated. All documentation and results can be presented in acomprehensive report that explains in detail the steps taken as well asthe results that were observed for each necessary parameter.

Design

Overall, the end result can be a sterilized lot of medical adhesive. Inorder to achieve this, a sterilization process can be validated per ANSIstandards. The sterilization process can be executed once to produce thelot for first demand. However, if need be, all of the documentation andinstructions will be in place to execute the sterilization process whenneeded.

The sterilization process is designed in a manner that can use used withstandard parts purchased from online retailers to keep cost at aminimum. Another way of keeping costs low is having the ability toexecute the process within, e.g., the duration of one 8-hour work day.

Sterilization Arrangement

The following example provides certain embodiments of procedures relatedto sterilization of medical adhesives and other compositions. As will beunderstood, these examples are illustrative, and the parameters,equipment, and procedures used can be varied in a myriad of waysdepending on the specific application.

The first step in the sterilization of the medical adhesive can bechoosing the means of sterilization. In some embodiments, ETO is notused in certain circumstances due to the fact that it might notpenetrate the glass vials in an efficient manner. That leaves both steamand dry heat as potential candidates in some embodiments.

The medical adhesive itself can be highly reactive to water and plasmaby design. This can causes concern with the steam method ofsterilization. If any steam penetrates the vial's septum or if there isa small amount of adhesive leaking out, the entire bottle's adhesive cancure while in the steam oven. Therefore, in some embodiments, dry heatcan be selected. While temperatures for dry heat processes can be higherthan for steam processes, dry heat processes reduce the risk of adhesivecuring. In some embodiments, a convection oven can be used, such as, forexample, a Blue M 146 series convection oven available on the market.

To determine the effectiveness of the sterilization process, biologicalindicators (BI) can be utilized in most or every cycle of the processqualification. In some embodiments, the BI include PT-1150, SGM BiotechSteril Amp II 5230. This is a self-contained ampoule with a populationof 10⁶ of temperature resistant bacteria, Bacillus Subtilis. It isdesigned to work (be tested) within, e.g., 110-118° C., which can beused in sterilization parameters of, for example, 115±5° C. PT-1150,SGM. The placement of the BIs can be in the most difficult to sterilizelocation, which is in the center of the vial. The vial size is 50 mm(height) by 15 mm (diameter). The BI size is 26 mm (height) by 6.5 mm(diameter). When placed inside the vial, the BI can be completelysubmerged and surrounded by the product that is being sterilized.

Sterilization Example

The following example provides certain embodiments of procedures relatedto sterilization of medical adhesives and other compositions. As will beunderstood, these examples are illustrative, and the parameters,equipment, and procedures used can be varied in a myriad of waysdepending on the specific application.

In some embodiments, Blue M 146 Series convection oven is used tosterilize medical adhesive in 6 ml vials. The vials can be arranged asindicated in FIG. 1A. FIG. 1A illustrates an embodiment of a loadconfiguration in a tray 100 that can be placed on a baking sheet. Insome embodiments, two or more trays 100 are placed into the convectionoven.

The BIs are placed in a number of vials, such as 11 vials. The BI's canbe completely submerged in medical adhesive. Five of the BI vials areloaded in a configuration on a first tray 100 as illustrated in FIG. 1Awith reference numbers 101, 102, 103, 104, and 105 indicating an exampleconfiguration. The other five BI vials are loaded in a sameconfiguration on a second tray 100 as illustrated in FIG. 1A withreference numbers 101, 102, 103, 104, and 105 indicating an exampleconfiguration, same as for the first tray 100. It is understood thatother load configurations of the vials on the tray are possible tosterilize or validate the sterilization process as discussed herein. Insome embodiments, the first and the second trays can have loadconfigurations that are different from each other. The 10 vials can belabeled for reference. The eleventh vial is the control and is notplaced in the oven (not loaded in the tray). All BIs, including thecontrol, can come from the same lot of BIs. If multiple BI lots areused, then 1 control BI & vial sample can be submitted for testing foreach BI lot. If there are not enough vials in the lot to complete theload, appropriate dunnage vials as discussed herein can be used to fillthe tray. Dunnage vials may be filled with, for example, tap water ormedical adhesive. The dunnage vials can be full in some embodiments. Thefirst and second tray 100 are placed on, for example, the 2nd and 4thshelves (from the top) in the oven with complete loads as illustrated inFIG. 1A.

The tray(s) 100 with the vials are placed into the oven. The oven isturned on for the temperatures and durations as discussed herein forsterilization (e.g., full cycle at nominal parameters including about agenerally linear, accelerating, or decelerating 10, 20, 30, 40, 50, or60 minute ramp up to 115±5° C. for a 2 hour sterilization period andremoval within about 30, 20, 15, 10 minutes, or less aftersterilization). After completion of the sterilization cycle, the vialsare cooled to 35° C. or less. In some embodiments, the BI vials are notbe refrigerated. The 11 BI vials (10 test units, 1 control) can besubmitted for 3rd party testing.

Another Sterilization Example

The following example provides certain embodiments of procedures relatedto sterilization of medical adhesives and other compositions. As will beunderstood, these examples are illustrative, and the parameters,equipment, and procedures used can be varied in a myriad of waysdepending on the specific application.

In some embodiments, a Blue M 146 Series convection oven is used tosterilize medical adhesive in 6 ml vials. The vials can be arranged asindicated in FIG. 1B. FIG. 1B illustrates an embodiment of a loadconfiguration in a tray 120 that can be placed on a baking sheet. Insome embodiments, two or more trays 120 are placed into the convectionoven.

Eleven (or more or less) product vials are selected randomly from thesterilization load to make BI vials. BI is inserted into each BI vialusing cleaned tweezers. The BIs are fully submerged in the adhesive. Tenof the BI vials are numbered from 1-10 on the cap and vial using, forexample, a permanent marker, and the remaining vial is labeled with a‘C’ as a control sample. All BIs, including the control, can come fromthe same lot of BIs. When multiple BI lots are used, then 1 control BIvial can be submitted for testing for each BI lot.

Five of the BI vials are loaded in a configuration on a first tray 120as illustrated in FIG. 1B with reference numbers 121, 122, 123, 124, and125 indicating an example configuration. The other five BI vials areloaded in a same configuration on a second tray 120 as illustrated inFIG. 1B with reference numbers 121, 122, 123, 124, and 125 indicating anexample configuration, same as for the first tray 120. Product vials 126are loaded the tray 120 as illustrated in FIG. 1B starting from thecenter working outwards. It is understood that other load configurationsof the vials on the tray are possible to sterilize or validate thesterilization process as discussed herein. In some embodiments, thefirst and the second trays can have load configurations that aredifferent from each other. The eleventh vial is the control and does notgo in the oven. When there is vial space remaining in the tray 120 afterloading the product vials 126, dunnage vials 127 can be used to fill thetray at the periphery as illustrated in FIG. 1B. Dunnage vials 127 maybe filled with, for example, tap water or medical adhesive. The dunnagevials 127 can be full in some embodiments. The product vials 127 anddunnage vials 127 are inspected to help ensure the vial and cap arecrack free and that the vial is filled to the appropriate level. Thefirst and second trays 120 are placed on, for example, the top andbottom shelves (from the top) in the oven with complete loads asillustrated in FIG. 1B.

The outer two perimeter rows on each rack are not used for product andfilled with dunnage vials 127. In some embodiments, the outer 1, 2, 3,4, 5, or more perimeter rows on each are not used for product and filledwith dunnage vials 127. The vials in or near the outer perimeter of thetray 120 can be subjected to higher and lower temperature extremes inthe oven than the vials toward the center of the tray 120. Keeping theproduct vial 126 toward the center of the tray 120 helps ensure thatsubstantially all or most of the product vials 126 are exposed to aboutthe same temperature.

The tray(s) 120 with the vials are placed into the oven. The oven isturned on for the temperatures and durations as discussed herein forsterilization (e.g., full cycle at nominal parameters including about agenerally linear, accelerating, or decelerating 10, 20, 30, 40, 50, or60 minute ramp up to 115±5° C. for a 2 hour sterilization period andremoval within about 30, 20, 15, 10 minutes, or less aftersterilization). After completion of the sterilization cycle, the vialsare cooled to 35° C. or less. In some embodiments, the BI vials are notbe refrigerated. The 11 BI vials (10 test units, 1 control) can besubmitted for 3rd party testing. Three percent (3%) of the lot's productvials 126 can be randomly selected (up to 10) and submitted to a 3rdparty lab, for example, for pyrogen testing using a limulus amebocytelysate (LAL) assay.

Engineering Protocol

An Engineering Protocol can include a validation plan for the dry heatsterilization of an adhesive. The Engineering Protocol can includecomponents of the validation process and the reasoning for each step.The parameters can be chosen through experimentation. Once theparameters are chosen, they can be used for every cycle after thevalidation is complete. In order to use different parameters on anofficial, released lot, the new parameters can be validated through aseparate validation plan. Additionally, a unique configuration of, forexample, 192 vials, can be used each time. The configuration can containall 192 vials or less in order to adhere to the validated process. Inimplementations where the desired lot is too small to fill out theconfiguration, “dummy” (or dunnage) vials can be used to complete theconfiguration. These “dummy” vials can be the exact size and shape ofthe actual vials and filled with an R&D lot of the adhesive or someother substance such as water. This can help ensure that the wholeconfiguration heats and cools as demonstrated within the processqualification.

The process qualification can utilize the overkill method, for example,in order to validate the dry heat sterilization process. The overkillmethod tests the half cycles of the process to ensure that the fullcycle can produce repeatable sterility as discussed herein. Three halfcycles can be performed at the nominal, minimum, and maximum parameters.One full cycle can be performed at the nominal parameters. If thesetests can exhibit zero or substantially zero bacterial growth, they canbecome a validated process. If specifications within the Installationand Operation Qualification (IOQ) and PQ are met or exceeded, thevalidation can be completed.

Example Engineering Protocol

The following example provides certain embodiments of procedures relatedto sterilization of medical adhesives and other compositions. As will beunderstood, these examples are illustrative, and the parameters,equipment, and procedures used can be varied in a myriad of waysdepending on the specific application.

In some embodiments, the Engineering Protocol is used to validate thedry heat sterilization process for medical adhesives. This sterilizationvalidation protocol can be executed to support sterility claims. Theparameters that control the sterilization process are exposure time andtemperature.

The parameters validated for the dry heat sterilization process ofmedical adhesive is 115° C.±5° for 4-4.5 hours. The configurationvalidated is a 192 vial configuration. This is the exact configurationthat some product lots can use. Dunnage vials are used to complete theload when lot sizes are smaller than the load configuration. FIG. 1Cillustrates an embodiment of a load configuration in a tray 110 placedon a baking sheet 112 that can be placed into an oven.

The sterilization oven used is a Blue M Forced Convection Oven. Theinstallation/operational qualification verifies that the oven functionswithin the parameters of the sterilization process. This includesverifying the oven operation consistency, temperature monitoringaccuracy, and alarm function. The process qualification utilizes theoverkill method in order to validate the dry heat sterilization process.The overkill method tests the half cycles of the process to ensure thatthe full cycle will produce repeatable sterility. Three half cycles areperformed at the nominal, minimum, and maximum parameters. One fullcycle is performed at the nominal parameters.

The dunnage vials can include various R&D (medical) adhesiveformulations. All of the different formulations replicate the thermalproperties of the various adhesives and therefore can be used torepresent adhesives used in the marketplace. Additionally, in someembodiments, these properties are not affected by repeatedly beingheated up and cooled down and therefore can be used until the vials showphysical flaws.

To determine the effectiveness of the sterilization process, biologicalindicators (BI) are utilized in every cycle of the processqualification. The BI utilized is PT-1150, SGM Biotech Steril Amp II5230 which is a self-contained ampoule with a population of 10⁶ oftemperature resistant bacteria, Bacillus Subtilis. The BI is designed towork (be tested) within 110-118° C., which is consistent withsterilization parameters of, for example, 115±5° C. The placement of theBIs can be in the most difficult to sterilize locations, which is in thecenter of the vial. The vial size is 50 mm (height) by 15 mm (diameter).The BI size is 25 mm (height) by 6.5 mm (diameter). When placed insidethe vial, the BI is completely submerged and surrounded by the productthat is being sterilized.

Each qualification test can meet the specifications as referenced ineach respective document. Both the IOQ and the PQ can be completed inorder for the sterilization process to be validated. Any units not usedfor testing from the sterilization validation lots can be released forclinical use, provided that full traceability is maintained and thesterilization validation results are as expected.

Bioburden is established and documented to ensure that the numbers andresistance of bioburden are within the allowable range for theparameters being used. For small batch sterilization of less than 10cubic feet, a minimum of BIs are used. Twelve BIs and an additionalnegative BI are distributed throughout the load. For small batchsterilizations of less than 10 cubic feet, three temperature sensors areused. In some embodiments, six temperature sensors are used to ensurethe uniformity of the chamber (less than 4 cubic feet).

IOQ can demonstrate that the equipment has been installed according tothe manufacturer's specifications and that the equipment operatesaccording to design specifications for performance, control systemfunction, and data collection systems associated with the equipment. Thephysical portion of the PQ can demonstrate that the sterilizationprocess is reproducible over the range of conditions proposed forroutine processing. The microbiological portion of the PQ candemonstrate that the sterilization process consistently achievessterility of 10⁻⁶ over the range of conditions proposed for routineprocessing.

Installation and Operation Qualification

The Installation and Operation Qualification (IOQ) can be used toprovide documented evidence that the equipment involved has beencorrectly installed and operating per the manufactures specifications.As discussed herein, in some embodiments, the piece of equipment usedfor the sterilization process is a Blue M Oven.

In some embodiments, the first step can be ensuring that the equipmentwas properly labeled and all appropriate documents present. This caninclude both tags from the manufacturer as well as from an adhesivedesigner. This checks to make sure that the equipment is properlyaccounted for within the quality system and therefore can be subjectedto all of the appropriate documentation. Included in the IOQ can be apreventative maintenance schedule that can be kept up to date for theduration of the equipment being used. Since the oven can be used for aprocess that will be validated, a “No Calibration Required” sticker canalso be present.

Once all of the paperwork had been taken care of, the oven can beinstalled. Installation can start at the source of power. A DigitalMulti Meter (DMM) can be used to check that the proper voltage is beingprovided for the unit. In some embodiments, once checked, the oven maynot be moved and/or used for production without a new IOQ beingexecuted. An initial visual inspection of all electrical components canalso ensure that the oven will be safely operating from the start. Afterthe IOQ, preventative maintenance can monitor this.

After the oven has been installed in its permanent location, it can beproved that it is performing as per the specifications detailed in theowner's manual. The first step can be powering the unit on and bringingthe oven up to a temperature. Next, it can be verified that the ovenproperly shuts off when it experiences power loss (pull out the plug).Once plugged back in, it may resume heating. Similar tests can be run toverify that the alarm system is in working condition.

An oven should be consistent in its performance. The oven can be mappedto verify that the heating is consistent throughout the chamber. To dothis, five (or more or less) thermocouples can be placed throughout thechamber and tested on three different levels. The oven can demonstrateeven heating to pass inspection. FIG. 2 illustrates an embodiment forplacement of thermocouples on a baking sheet and/or oven rack 112 tomeasure a temperature gradient of the oven. Five thermocouples arelocated on the baking sheet 112 as indicated by reference numbers 114,115, 116, 117, and 118 in FIG. 2. The IOQ document can be completed andfiled with quality assurance before moving on to the parameter testing.

Parameter Testing

In order to determine the appropriate parameters for the sterilizationprocess, several tests can be completed to help verify the acceptabilityof each option. In some embodiments, the variables include time exposedto the heat and temperature of the oven. Half cycles durations of 2, 3and 4 hours can be used with temperatures of, for example, 120 and 130°C. Half cycle times can be used in order to exercise the overkill methodas discussed herein. In some embodiments, the cycle time can vary fromabout 1-8 hours, including about 2-7 hours, including about 1, about 2,about 3, about 4, about 5, about 6, about 7, or about 8 hours, includingranges bordering and the foregoing values. The temperatures can varyfrom about 100 to about 200° C., including about 100 to about 120° C.,including about 110 to about 120° C., including about 110 to about 140°C., including about 120 to about 130° C., including about 120 to about180° C., including about 140 to about 160° C., including about 100,about 105, about 110, about 115, about 120, about 125, about 130, about135, about 140, about 145, about 150, about 155, about 160, about 165,about 170, about 175, about 180, about 185, about 190, and about 195°C., including ranges bordering and the foregoing.

Throughout the duration of the parameter testing, six biologicalindicators can be used, one for each combination of parameters. Twelvevials filled with the medical adhesive can be used in testing. One vialmay have a biological indicator placed within it; another may have athermocouple placed within it through a slit in the septum. The testingcan be done in random order and the oven may be allowed to completelycool in between tests to help ensure accuracy.

After test runs are completed, the self-contained biological indicatorsas well as a negative control can be sent to a laboratory such as, forexample, Micromed Laboratories, to undergo resistance performancetesting. The BI's can be incubated at, for example, about 40 to about70° C., including about 55 to about 60° C., including ranges borderingand the foregoing values, for about 1 to about 10 days, including about2 to about 7 days, including 48 hours, including ranges bordering andthe foregoing values. If the samples show no or substantially nobacterial growth, the tested parameters may be acceptable to moveforward with. The shortest cycle time at the lowest possible temperaturecan be selected reduce degradation and costs as well as adhesive curingas discussed herein. Additional tests may be performed to pursue optimalparameters.

A test can include two runs at 110° C. for 2 hours. The same proceduremay be followed as the previous tests and produce similar results. Insome embodiments, the cycle time can be 2 hours at a minimum temperatureof 110° C.

Process Qualification/Validation

A Process Qualification (PQ) can provide instructions for the processqualification of the dry heat sterilization of the medical adhesive. PQcan outline the details of the three half cycle tests as well as the onefull cycle test that will validate the process per the ANSI standard.

Each test can include a full 192 vial configuration with 12 BI's withinvials. The configuration can be placed, for example, in the middle ofthe third rack from the bottom of the Blue M 146 series convection oven.The three half cycles can use “dummy” vials to fill out theconfiguration, while the full cycle can use actual adhesive. Therefore,if all tests pass, the resultant may not only be a validated process,but also a sterilized lot of medical adhesive.

As an example, a minimum half cycle can be performed at 110° C.,followed by a nominal and maximum half cycle at, for example, 120 and130° respectively. Then a full 4 hour cycle at the nominal temperaturecan be executed. For the duration of these tests, once the oven gets upto temperature, it can remain within 5 degrees of the desiredtemperature to be valid.

Throughout the test, readings from the six thermocouples placed in vialswithin the configuration can be recorded. Once completed, the BI's canbe dropped off at a laboratory as discussed herein for testing. In orderfor the process to be validated, all 48 BIs should show zero orsubstantially zero signs of bacterial growth after incubation.

Example Process Qualification Procedure

The following example provides certain embodiments of procedures relatedto sterilization of medical adhesives and other compositions. As will beunderstood, these examples are illustrative, and the parameters,equipment, and procedures used can be varied in a myriad of waysdepending on the specific application.

In some embodiments, the PQ uses the overkill method to validate the dryheat sterilization process. By testing three batches at the half cycles,it can be determined that the full cycle will produce a sterile productconsistently. In some embodiments, the BIs can be stored in therefrigerator. Prior to testing, the BI's can be brought to roomtemperature before being exposed to the sterilization cycle.

FIG. 6 illustrates a process flow diagram of an embodiment of a processqualification procedure 190. In some embodiments, minimum parametertesting for 2 hours (half cycle) 191 includes the following. The oven isturned on to 110° C. and the alarm is set to 120° C. A 192 vial loadconfiguration is arranged in a tray 130 as illustrated in FIG. 3. FIG. 3illustrates an embodiment of a load configuration in a tray 130.Nineteen vials are filled with a first medical adhesive. 173 dunnagevials are filled with a second medical adhesive that can be the same,similar, or different from the first medical adhesive. Six thermocouplesare arranged on the tray 130 as illustrated in FIG. 3 as T1, T2, T3, T4,T5, and T6 indicating an example configuration. It is understood thatother thermocouple arrangements and configurations on the tray 130 arepossible to measure or sample the temperature of the vials duringsterilization. The thermocouples can placed into the vials by slicing aslit into the septum of the vials with a razor blade and sliding thethermocouples into the vials through the slit in the septum. BI vialsare loaded on the tray 130 as illustrated in FIG. 3 with referencenumber 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 indicating an exampleconfiguration. A negative control BI is loaded on the tray 130 asillustrated in FIG. 3 with reference N indicating an exampleconfiguration. It is understood that other load configurations of thevials on the tray 130 are possible to qualify or validate thesterilization process as discussed herein. The vials can be labeled toindicate the various vials loaded in the tray 130 as discussed herein.When the oven temperature has reached the sterilization temperature, thebaking sheet and tray are placed onto the third rack from the bottom ofthe oven and slid back until the baking sheet is in the middle of theoven. In some embodiments, the tray is placed into the oven during warmup to the sterilization temperature. Each thermocouple is connected to athermometer. Observations can be recorded every 15 minutes for 2 hours.The vials can remain at 110±5° C. once the temperature has been reached.Once the cycle is complete, the vials are allowed to return to roomtemperature. In some embodiments, once at room temperature, theBI-containing vials can be stored in a refrigerator until sent to a labfor analysis 196.

In some embodiments, nominal parameter testing for 2 hours (half cycle)192 includes the following. The oven is turned on to 115° C. and thealarm is set to 125° C. The same procedures as discussed above forminimum parameter testing can be followed. The vials can remain at115±5° C. once the temperature has been reached. In some embodiments,once at room temperature, the BI-containing vials can be stored in arefrigerator until sent to a lab for analysis 196.

In some embodiments, maximum parameter testing for 2 hours (half cycle)194 includes the following. The oven is turned on to 120° C. and thealarm is set to 130° C. The same procedures as discussed above forminimum parameter testing can be followed. The vials can remain at120±5° C. once the temperature has been reached. In some embodiments,once at room temperature, the BI-containing vials can be stored in arefrigerator until sent to a lab for analysis 196.

In some embodiments, full cycle at nominal parameters for 4 hours 195includes the following. The oven is turned on to 115° C. and the alarmis set to 125° C. A 192 vial load configuration is arranged in a tray130 as illustrated in FIG. 3. All vials can be filled with medicaladhesive. No dunnage vials are used. Six thermocouples are arranged onthe tray 130 as illustrated in FIG. 3 as T1, T2, T3, T4, T5, and T6indicating an example configuration. It is understood that otherthermocouple arrangements and configurations on the tray 130 arepossible to measure or sample the temperature of the vials duringsterilization. The thermocouples can placed into the vials by slicing aslit into the septum of the vials with a razor blade and sliding thethermocouples into the vials through the slit in the septum. BI vialsare loaded on the tray 130 as illustrated in FIG. 3 with referencenumber 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 indicating an exampleconfiguration. A negative control BI is loaded on the tray 130 asillustrated in FIG. 3 with reference N indicating an exampleconfiguration. It is understood that other load configurations of thevials on the tray are possible to qualify or validate the sterilizationprocess as discussed herein. The vials can be labeled to indicate thevarious vials loaded in the tray 130 as discussed herein. When the oventemperature has reached the sterilization temperature, the baking sheetand tray are placed onto the third rack from the bottom of the oven andslid back until the baking sheet is in the middle of the oven. In someembodiments, the tray is placed into the oven during warm up to thesterilization temperature. Each thermocouple is connected to athermometer. Observations can be recorded every 15 minutes for 4 hours.The vials can remain at 115±5° C. once the temperature has been reached.Once the cycle is complete, the vials are allowed to return to roomtemperature. Once at room temperature, the BI-containing vials canpackaged in such a way as to help ensure the vials remain upright fordelivery to a lab for analysis to check for no or substantially nobacterial growth 196.

Another Example Process Qualification Procedure

The following example provides certain embodiments of procedures relatedto sterilization of medical adhesives and other compositions. As will beunderstood, these examples are illustrative, and the parameters,equipment, and procedures used can be varied in a myriad of waysdepending on the specific application.

Sterilization of a medical adhesive is accomplished using a lowtemperature dry heat process. It has been found that sterilization ofthe adhesive at 115±5° C. does not significantly degrade the product andhas previously been validated with a process differing in the overallmass of product sterilized and time of sterilization. FIG. 6 is aprocess flow diagram of an embodiment of a process qualificationprocedure 190.

In some embodiments, the qualification procedure 190 uses the overkillmethod to validate the sterilization process at the required temperaturefor a sterilization time of 2 hours. The adhesive is packaged in 6 mlvials with 320 units placed in a ventilated tray 140 as illustrated inFIG. 4. Example biological indicators (BIs) for qualification testinginclude Raven 1-6100TT and 3-6100TT. By using the overkill method totest three batches at the half cycle (min, nominal, max for 1 hour), itcan be determined that the full cycle can consistently produce sterileproduct.

The following tests are conducted: (A) One test 320 6 ml vials for 1hour at minimum conditions 191 with Raven 1-6100TT; (B) One test of 3206 ml vials for 1 hour at nominal conditions 192 with Raven 1-6100TT andRaven 3-6100T; (C) One test of 320 6 ml vials for 1 hour at maximumconditions 194 with Raven 1-6100TT; (D) One test of 320 6 ml vials for 2hours at nominal conditions 195 with Raven 1-6100TT and Raven 3-6100T.

FIG. 4 illustrates an embodiment of a load configuration in a tray 140with a single BI type. 321 vials total are placed in the tray 140 on the3rd shelf from the bottom of the Blue M Oven including: (A) 10 vials arefilled with medical adhesive and BIs and loaded in a configuration asillustrated in FIG. 4 with reference numbers 141, 142, 143, 144, 145,146, 147, 148, 149, and 1410 indicating an example configuration; (B) 1vial is filled with medical adhesive and a BI placed inside to be acontrol—this vial does not go in the oven but is sent for testing withthe above 10 BI vials; (C) 5 vials are filled with TEC (triethylcitrate) with holes drilled in the caps for thermocouple placement andloaded in a configuration as illustrated in FIG. 4 with reference number151, 152, 153, 154, and 155 indicating an example configuration; (D)dunnage vials are filled with water.

Ten BI samples are placed in the sterilization tray 140 as shown in FIG.4. Additionally, one control BI from the same lot as the previous 10 BIsis used as a control. Five thermocouples are used to monitor temperatureat the four corners and the center of the sterilization tray 140. Watercan be a viable substitute for the adhesive in the dunnage vials becausewater can have a higher heat capacity than some medical adhesives. TECis used in the vials containing thermocouples because it has a 300° C.(testing runs at 125° C. max) boiling point to reduce blowing bythermocouple-to-vial seals at sterilization temperature.

FIG. 5 illustrates an embodiment of a load configuration in a tray 160with two BI types. Using two types biological indicators (BI) can helpincrease validation/qualification efficacy and test for sterilizationeffectiveness for possible various types of bacterial growth. In someembodiments, more than two, including three, four, five or more BIs maybe used to help increase validation/qualification efficacy and test forsterilization effectiveness for possible various types of bacterialgrowth. 322 vials total are placed in the tray 160 on the 3rd shelf fromthe bottom of the Blue M Oven including: (A) 20 are filled with SCA andBI's and labeled as indicated for the two BI types in the diagram belowas illustrated in FIG. 5 with reference numbers 161, 162, 163, 164, 165,166, 167, 168, 169, and 1610 indicating an example configuration for the1-6100TT BI vials and 171, 172, 173, 174, 175, 176, 177, 178, 179, and1710 indicating an example configuration for 3-6100TT BI vials; (B) 3vials are filled with a medical adhesive, a 1-6100TT BI in medicaladhesive, and a 3-6100TT BI in medical adhesive as controls—these vialsdo not go in the oven but are sent for testing with the above 20 BIvials; (C) 5 vials are filled with TEC with holes drilled in the capsfor thermocouple placement and loaded in a configuration as illustratedin FIG. 5 with reference number 181, 182, 183, 184, and 185 indicatingan example configuration; (D) dunnage vials are filled with water.

Twenty BI samples are placed in the sterilization tray 160 as shown inFIG. 5. Additionally, one control BI from the same lot as the previous20 BIs is used as a control. Five thermocouples are used to monitortemperature at the four corners and the center of the sterilization tray140. Water can be a viable substitute for the adhesive in the dunnagevials because water can have a higher heat capacity than some medicaladhesives. TEC is used in the vials containing thermocouples because ithas a 300° C. (testing runs at 125° C. max) boiling point to reduceblowing by thermocouple-to-vial seals at sterilization temperature.

In some embodiments, minimum conditions, half cycle testing for 1 hour191 includes the following. The BI's are not refrigerator either beforeor after testing. Upon opening a BI, it is placed directly into the testvial. The BI is verified to be completely submerged in the medicaladhesive before tightly screwing on vial cap. The oven is turned on to110° C. and the alarm is set to 120° C. The vials are loaded on the trayas discussed above. Dunnage vials are verified to be 90%+ filled withtap water and the cap screwed on. Vials containing BIs are filled withmedical adhesive and the cap screwed on. Vials containing thermocouplesare filled with TEC and drilled through caps screwed on. In someembodiments, the vial initial temperature can start at between 17-35° C.When the oven temperature has reached the sterilization temperature, thebaking sheet and tray are placed onto the third rack from the bottom ofthe oven and slid back until the baking sheet is in the middle of theoven. In some embodiments, the tray is placed into the oven during warmup to the sterilization temperature. Each thermocouple is connected to athermometer. The timer is started once all thermocouples reach at least105° C. Observations can be recorded every 15 minutes for 1 hour. Thevials can remain at 110±5° C. once the temperature has been reached.Once the cycle is complete, the vials are allowed to return to roomtemperature. Once at room temperature, the BI-containing vials are sentto a lab for analysis.

In some embodiments, nominal conditions, half cycle testing for 1 hour192 includes the following. The oven is turned on to 115° C. and thealarm is set to 125° C. The same procedures as discussed above forminimum conditions testing can be followed. The timer is started onceall thermocouples reach at least 110° C. Observations can be recordedevery 15 minutes for 1 hour. The vials can remain at 115±5° C. once thetemperature has been reached.

In some embodiments, maximum conditions, half cycle testing for 1 hour194 includes the following. The oven is turned on to 120° C. and thealarm is set to 130° C. The same procedures as discussed above forminimum conditions testing can be followed. The timer is started onceall thermocouples reach at least 115° C. Observations can be recordedevery 15 minutes for 1 hour. The vials can remain at 120±5° C. once thetemperature has been reached.

In some embodiments, nominal conditions, full cycle testing for 2 hours195 includes the following. The oven is turned on to 115° C. and thealarm is set to 125° C. The same procedures as discussed above forminimum conditions testing can be followed. The timer is started onceall thermocouples reach at least 110° C. Observations can be recordedevery 15 minutes for 2 hour. The vials can remain at 115±5° C. once thetemperature has been reached.

FIG. 7 illustrates a graph showing representative temperature profilesfor an embodiment of a load configuration in an oven during asterilization process as discussed herein. In some embodiments, thereare ten thermocouples for a given load configuration as in the aboveembodiments of FIGS. 4 and 5. For example, five vials are filled withTEC (triethyl citrate) with holes drilled in the caps for thermocoupleplacement and loaded in a configuration as illustrated in FIG. 4 withreference number 151, 152, 153, 154, and 155 indicating an exampleconfiguration. As another example, five vials are filled with TEC withholes drilled in the caps for thermocouple placement and loaded in aconfiguration as illustrated in FIG. 5 with reference number 181, 182,183, 184, and 185 indicating an example configuration. In someembodiments, more or less than five thermocouples per tray may be used.Two trays can be loaded into the oven. In some embodiments, one or morethan two trays may be loaded into the oven.

The temperature profile illustrated in FIG. 7 of the ten thermocouplesshows that the vials are heated substantially uniformly throughout thesterilization process with an initial ramp-up period and post cool-downperiod as discussed herein. Substantially uniform temperaturedistribution helps ensure efficacy and validation of the sterilizationprocess as discussed herein. In some embodiments, the thermocouples fora given load configuration stay within about a 10° C. range of eachother. In some embodiments, the thermocouples for a given loadconfiguration may stay within about a 5 to about 20° C., including abouta 7 to about 15° C., range of each other, including ranges bordering andthe foregoing values.

The foregoing procedures can produce one sterile lot of medical adhesiveready for first demand. After the vials that contained the BIs andthermocouples are discarded, the lot size 173 vials can be documentedand stored in a cool, dry place. Some vials can undergo additionaltesting to ensure that the adhesive formulation still performs to thesame standards as it did before the process.

In some embodiments, a full cycle time of about 4 hours can lead to theentire process to being done in one day. This can includes 2 hours forfilling up the vials, 4 hours in the oven and 1 hour to cool down. Thus,in one work day the adhesive can easily go from a single container, toindividual vials all sterilized by a validated process.

In some embodiments, the full cycle time can be about 2 hours which canlead to the entire process to being done in one day. This can includes 2hours for filling up the vials, 2 hours in the oven and 1 hour to cooldown. Thus, in one work day the adhesive can easily go from a singlecontainer, to individual vials all sterilized by a validated process. Insome embodiments, the full cycle time can be less than 2 hours, betweenabout 2 to about 4 hours, or more than 4 hours.

Running the process again incurs primarily the additional costs ofpowering the oven and to pay an employee a day's worth of wages. Thiscan be due to the fact that all fixtures and trays being used in theprocess can be reused for every future run. Moreover, the cost ofrunning the oven may be negligible.

With the process is in place, it can be used when needed. As per thestandard, the oven can be dedicated to this process and as long as it isnot moved to a different location, it can sterilize a new lot. If thereare any changes in the formulation of the adhesive or if a new packagingmethod are established instead of the vials, further sterilizationand/or validation processes may be developed. In either of these cases,a new validation may be executed in order to comply with ANSI standards.However, much of the work needed to be done for the validation will becompleted already. The parameters and configuration can remain the same.But the PQ will need to be performed with whatever new changes to theformulation or vial that have been implemented.

In some embodiments, the process can be characterized as follows: (A)The whole cycle of filling the vials and sterilizing them can becompleted in one 8-hour work day; (B) The lot size is large enough tomeet needs without having to execute multiple runs; (C) The wholevalidation can be completed for a fraction of the cost compared toquotes received from vendors; (D) The established quality systems inplace can be maintained; (E) The process can be validated per ANSIstandards; and (F) One sterilized lot of medical adhesive can be readyfor first demand clinical trials

Sterilization of adhesives as disclosed herein and/or its packaging canbe accomplished by various methods. These methods include chemical,physical, and/or irradiation methods. Examples of chemical methodsinclude exposure to ethylene oxide or hydrogen peroxide vapor. Examplesof physical methods include sterilization by heat. In some embodiments,an adhesive can be heat-sterilized at a temperature of less than about170° C., 160° C., 150° C., 140° C., 130° C., 120° C., 110° C., or less.In one embodiment, an adhesive can be heat-sterilized at a temperatureof between about 100° C. and 120° C. for less than about 240 minutes,180 minutes, 150 minutes, 135 minutes, 120 minutes, 110 minutes, 100minutes, 90 minutes, or less. Examples of irradiation methods includegamma irradiation, electron beam irradiation, and microwave irradiation.

The foregoing detailed description has set forth various embodiments ofthe systems and/or methods via the use of figures and/or examples.Insofar as such figures and/or examples contain one or more functionsand/or operations, it will be understood by those within the art thateach function and/or operation within figures or examples can beimplemented individually and/or collectively. The herein-describedsubject matter sometimes illustrates different components containedwithin, or connected with, different other components. It is to beunderstood that such depicted architectures are merely examples, andthat in fact many other architectures can be implemented which achievethe same functionality. In a conceptual sense, any arrangement ofcomponents to achieve the same functionality is effectively “associated”such that the desired functionality is achieved. Hence, any twocomponents herein combined to achieve a particular functionality can beseen as “associated with” each other such that the desired functionalityis achieved, irrespective of architectures or intermedial components.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity.

It will be understood by those within the art that, in general, termsused herein, are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced embodiment recitation is intended, suchan intent will be explicitly recited in the embodiment, and in theabsence of such recitation no such intent is present. For example, as anaid to understanding, the disclosure may contain usage of theintroductory phrases “at least one” and “one or more” to introduceembodiment recitations. However, the use of such phrases should not beconstrued to imply that the introduction of an embodiment recitation bythe indefinite articles “a” or “an” limits any particular embodimentcontaining such introduced embodiment recitation to embodimentscontaining only one such recitation, even when the same embodimentincludes the introductory phrases “one or more” or “at least one” andindefinite articles such as “a” or “an” (e.g., “a” and/or “an” shouldtypically be interpreted to mean “at least one” or “one or more”); thesame holds true for the use of definite articles used to introduceembodiment recitations. In addition, even if a specific number of anintroduced embodiment recitation is explicitly recited, those skilled inthe art will recognize that such recitation should typically beinterpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, typicallymeans at least two recitations, or two or more recitations).Furthermore, in those instances where a convention analogous to “atleast one of A, B, and C, etc.” is used, in general such a constructionis intended in the sense one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, and C”would include but not be limited to systems that have A alone, B alone,C alone, A and B together, A and C together, B and C together, and/or A,B, and C together, etc.). In those instances where a conventionanalogous to “at least one of A, B, or C, etc.” is used, in general sucha construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, or C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, embodiments, or drawings, should be understood tocontemplate the possibilities of including one of the terms, either ofthe terms, or both terms. For example, the phrase “A or B” will beunderstood to include the possibilities of “A” or “B” or “A and B.”

Although the present invention has been described herein in terms ofcertain embodiments, and certain exemplary methods, it is to beunderstood that the scope of the invention is not to be limited thereby.Instead, the Applicant intends that variations on the methods andmaterials disclosed herein which are apparent to those of skill in theart will fall within the scope of the Applicant's invention.

1-9. (canceled)
 10. A method for sterilizing a medical adhesive, themethod comprising: enclosing the medical adhesive in a first housing,the first housing configured to seal the medical adhesive; positioningthe first housing with the medical adhesive in a tray, the trayconfigured to secure the first housing in a first predetermined positionon the tray; positioning the tray with the first housing on an ovenrack, the oven rack inside an oven; and operating the oven to sterilizethe medical adhesive, wherein following sterilization of the medicaladhesive, a post-sterilization viscosity of the medical adhesive iswithin about 5% of a pre-sterilization viscosity of the medicaladhesive.
 11. The method of claim 10, further comprising: enclosing abiological indicator in a second housing, the second housing configuredto seal the biological indicator, the biological indicator configured toindicate whether sterilization has been achieved; and positioning thesecond housing with the biological indicator in the tray, the trayconfigured to secure the second housing in a second predeterminedposition on the tray.
 12. The method of claim 11, wherein the biologicalindicator is enclosed in the second housing with the medical adhesive,and wherein the medical adhesive substantially surrounds the biologicalindicator.
 13. The method of claim 10, further comprising: enclosing themedical adhesive in a first plurality of housings, the first pluralityof housings configured to seal the medical adhesive; and positioning thefirst plurality of housings with the medical adhesive in the tray, thetray configured to secure the first plurality of housing in a firstplurality of predetermined positions on the tray.
 14. The method ofclaim 13, wherein the first plurality of housings are heated tosubstantially a same temperature over the time duration.
 15. The methodof claim 14, wherein the first plurality of predetermined positionsstart at a center of the tray and radiate toward the perimeter as thefirst plurality of housing are positioned in the tray to help providethe same temperature over the time duration.
 16. The method of claim 13,further comprising: enclosing a substance not for patient application ina second plurality of housings, the second plurality of housingsconfigured to seal the substance; and positioning the second pluralityof housings with the substance in the tray, the tray configured tosecure the second plurality of housing in a second plurality ofpredetermined positions on the tray; wherein the second plurality ofpredetermined positions are substantially at a perimeter of the tray.17. The method of claim 10, wherein the medical adhesive comprises acyanoacrylate.
 18. The method of claim 10, wherein the oven is operatedto have a ramp-up time of about 40 minutes to a predeterminedtemperature profile for sterilizing the medical adhesive.
 19. A methodfor sterilizing a medical adhesive, the method comprising: enclosing themedical adhesive in a first housing, the first housing configured toseal the medical adhesive; positioning the first housing with themedical adhesive within an oven; and operating the oven to sterilize themedical adhesive, wherein following sterilization of the medicaladhesive, a post-sterilization viscosity of the medical adhesive iswithin about 5% of a pre-sterilization viscosity of the medicaladhesive.
 20. The method of claim 19, further comprising: enclosing abiological indicator in a second housing, the second housing configuredto seal the biological indicator, the biological indicator configured toindicate whether sterilization has been achieved; and positioning thesecond housing with the biological within the oven.
 21. The method ofclaim 20, wherein the biological indicator is enclosed in the secondhousing with the medical adhesive, and wherein the medical adhesivesubstantially surrounds the biological indicator.
 22. The method ofclaim 19, wherein the medical adhesive comprises a cyanoacrylate. 23.The method of claim 19, wherein the oven is operated to have a ramp-uptime of about 40 minutes to a predetermined temperature profile forsterilizing the medical adhesive.
 24. A method for sterilizing a medicaladhesive, the method comprising: enclosing the medical adhesive in afirst housing, the first housing configured to seal the medicaladhesive; positioning the first housing with the medical adhesive withinan oven; measuring a pre-sterilization viscosity of the medicaladhesive; operating the oven to sterilize the medical adhesive; andmeasuring a post-sterilization viscosity of the medical adhesive,wherein following sterilization of the medical adhesive, thepost-sterilization viscosity is within about 5% of the pre-sterilizationviscosity of the medical adhesive.
 25. The method of claim 24, furthercomprising: enclosing a biological indicator in a second housing, thesecond housing configured to seal the biological indicator, thebiological indicator configured to indicate whether sterilization hasbeen achieved; and positioning the second housing with the biologicalindicator within the oven.
 26. The method of claim 25, wherein thebiological indicator is enclosed in the second housing with the medicaladhesive, and wherein the medical adhesive substantially surrounds thebiological indicator.
 27. The method of claim 24, wherein the medicaladhesive comprises a cyanoacrylate.
 28. The method of claim 24, whereinthe oven is operated to have a ramp-up time of about 40 minutes to apredetermined temperature profile for sterilizing the medical adhesive.29. The method of claim 24, further comprising: enclosing a substancenot for patient application in a plurality of housings, the plurality ofhousings configured to seal the substance; and positioning the pluralityof housings around the first housing within the oven.